Aging of the immune system leads to diminished ability to respond to and clear pathogens and tumors believed to significantly contribute to morbidity and mortality in older individuals. It has been repeatedly shown that numerous T-cell functions are diminished or dysregulated in old age, however, despite intense research, gaps in the understanding of T-cell senescence still exist. Specifically, we do not fully understand the nature of homeostatic changes, the distinction between primary and secondary changes, nor the relative influence and the interplay between cellular and microenvironmental changes. This lack of knowledge precludes identification of the effective points of intervention to circumvent or reverse the age-related defects in immune function. The above gap in understanding T-cell senescence is still more pronounced as it relates to human senescence. To bridge the above gap, this project proposes to study in RM the evolution with age of T-cell response to new antigens by monitoring them following primary, secondary, memory and recall phases of the response. CD4 and CD8 T-cell responses will be measured by testing key phenotypic and functional parameters, in T-cells, including activation, in vivo proliferation and turnover, and development and maintenance of effector function. All experiments will evaluate strength (response intensity), threshold (sensitivity to different Ag doses) and kinetics of the response. Thereby, they will test a main hypothesis: that the key defect(s) lies in qualitative changes in naive CD8 T-cell responses; and two secondary hypotheses: (i) that T-cell clonal expansions (TCE) are associated with impaired primary T-cell responses; and (ii) that age-related dominance of memory CD8 T-cells is in part due to accumulation of Ag-specific cells with blunted effector function. Results from these studies should bring closer the long-term goal of this project, to improve T-cell immunity in the elderly.